Melanoma is less common than other skin cancers. However, it is much more dangerous if it is not found early. It causes the majority (75%) of deaths related to skin cancer. Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. It is more common in women than in men. It is particularly common among Caucasians, especially northwestern Europeans living in sunny climates. There are high rates of incidence in Oceania, Northern America, Europe, southern Africa, and Latin America, with a paradoxical decrease in southern Italy and Sicily. This geographic pattern reflects the primary cause, ultraviolet light (UV) exposure crossed with the amount of skin pigmentation in the population. According to a WHO report, about 48,000 melanoma-related deaths occur worldwide per year (Lucas et al., 2006, Environmental Burden of Disease Series. 13. World Health Organization). The treatment includes surgical removal of the tumor. If melanoma is found early, while it is still small and thin, and if it is completely removed, then the chance of cure is high. The likelihood of the melanoma coming back or spreading depends on how deeply it has gone into the layers of the skin. For melanomas that come back or spread, treatments include chemo- and immunotherapy or radiation therapy.
Metastatic melanoma is a poor-prognosis disease. This cancer has the steepest incidence rate worldwide and considering skin cancers, it is the first cause of mortality with up to 12,200 deaths expected in 2012 (American Cancer Society, 2008, Cancer Facts and Figures). The five-year survival rate is 5-10 percent and the median survival is 6 to 10 months (Balch et al., 2009, J Clin Oncol; Tsao et al., 2004, N Engl J Med). Until the recent development of new drugs such as immunotherapy and anti-BRAF targeted agents, no therapy had been able to demonstrate any significant overall survival benefit in patients with metastatic melanoma (Hodi et al., 2010, N Engl J Med; Chapman et al., 2001, N Engl J Med).
Ipilimumab (Yervoy®) and Tremelimumab are monoclonal antibodies directed against cytotoxic T-lymphocyte-associated antigen 4. These fully human antibodies (IgG1κ) downregulate an inhibitory pathway of T lymphocytes, and potentiate the immune response against melanoma cells (Kaehler et al., 2010, Semin Oncol). Ipilimumab in particular improves overall survival in patients with pretreated metastatic melanoma (Hodi et al., 2010, N Engl J Med). In this phase III randomized trial the median overall survival was 10.1 months in the Ipilimumab group (at the dose of 3 mg/kg), versus 6.4 months in the gp 100 group. Robert et al. showed in another randomized phase III trial that Ipilimumab at the dose of 10 mg/kg, in combination with dacarbazine, was associated with a longer overall survival than dacarbazine alone (11.2 months versus 9.2 months respectively) in previously untreated metastatic melanoma patients (Robert et al., 2011, N Engl J Med). These studies led to the approval of Ipilimumab by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) as a second-line treatment of metastatic melanoma.
The issues encountered during clinical trials are noteworthy. First, the safety profile is unusual with new autoinflammatory side effects called immune-related adverse events (irAEs) (Weber et al., 2009, Cancer Immunol Immunother). The cutaneous and gastrointestinal irAEs are frequent, respectively 40% and 30% of patients, and can be life-threatening (Di Giacomo et al., 2010, Semin Oncol). Hodi et al. reported 12% of grade 3-4 severe colitis and 14 drug-related deaths (2.1%) in 643 patients receiving Ipilimumab (Hodi et al., 2010, N Engl J Med). The irAEs are dose-dependent, are usually manageable with high-dose corticosteroids and might, in severe and steroid-resistant cases, require more potent immunosuppressive drugs like anti-TNF-α (Wolchock et al., 2010, Lancet Oncol; Weber et al., 2012, J Clin Oncol). Secondly, patterns of response to Ipilimumab are different from those to cytotoxic agents. New criteria of evaluation have been developed to replace the Response Evaluation Criteria in Solid Tumors (RECIST, WHO Criteria) that are more adapted to immunotherapeutic agents or molecules. Indeed, Ipilimumab and other immunotherapeutic agents, like anti-programmed death-1 (anti-PD-1) monoclonal antibodies, are now commonly evaluated using the so-called “immune-related response criteria” (Wolchock et al., 2009, Clin Cancer Res). Thus, initial increase in tumor burden and delayed clinical response are new profiles that may not require discontinuation of Ipilimumab.
While about 15-20% of patients are long-term responders, the clinical use of Ipilimumab is currently hampered by two main problems: i) side effects as explained previously (indeed, up to 30% patients develop adverse immune related side effects, such as diarrhea, colitis, hypophysitis, skin erythroderma, fatigue and three case reports of agranulocytosis, etc., sometimes steroid-resistant and precluding the continuation of the treatment); and ii) the cost of the therapy which is 94,000 dollars/4 injections (while a responder needs more than a year of therapy administered every 3 weeks up to stabilization or cure and then every 2 months as a maintenance therapy). So far, the lymphocyte counts, the eosinophile counts and/or the percentages of Inducible T Cell Costimulator (ICOS) expressing CD4+ T cells after one or two cycles of therapy appear to indicate responders from non-responders. However, none of these above-quoted markers represent a biomarker of high specificity and positive predictive value. Hence, there is an unmet medical need for an efficient predictive marker of response and/or toxicity, which would decrease the percentage of cancer patients suffering from immune-related adverse events but failing to respond to the selected anti-cancer drug(s), or worse being further affected or poisoned by the selected anti-cancer drug(s).